Abstract

Background: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors α/β (PDGFRα/β). FGF aberrancy, as defined by amplification of either FGFR1, or 11q (containing FGF ligands 3, 4, CCND1, and 19), or both, is a hallmark genomic alteration that can be observed in up to 25% of patients with breast cancer. In a phase I clinical trial of lucitanib at daily doses of 5 to 20 mg, heavily pretreated patients with advanced breast cancer patients and FGF aberrancy experienced an objective response rate (ORR) of 50% and a median progression-free survival (PFS) over 9 months (Soria et al, 2014). This compelling clinical activity has led to the initiation of a global clinical development program for lucitanib in breast cancer.

Trial design: this is a phase II trial testing the efficacy of lucitanib at the dose of 15 mg daily in patients with ER+/HER2- metastatic breast cancer who have received at least one first-line systemic anticancer therapy in the metastatic setting. After informed consent, metastatic tissue (fresh biopsy or archival) is centrally evaluated by FISH for FGFR1- and/or 11q- amplification. Based on FISH results, patients are allocated to cohort 1 (FGFR1-amp), cohort 2 (11q-amp) or cohort 3 (neither). Patients with dual amplification are allocated to cohort 1. The primary objective is to evaluate the ORR of single agent lucitanib in the three cohorts. Secondary objectives include clinical benefit rate, PFS, safety and pharmacokinetics in addition to exploratory biomarker analyses. A Simon two-stage design will be used for each of the cohorts to test the null hypothesis that the ORR is 5% or less versus 20% using a one-sided test with 5% level of significance and 90% power. In each cohort separately, an initial 21 patients with measurable disease at baseline will be assessed at the end of stage 1. If at least 2 patients respond per the pre-specified criteria, this cohort will accrue additional 20 patients. The null hypothesis will be rejected if there are at least 5 responders among all 41 patients.

Eligibility Criteria: ER+/HER2- metastatic breast cancer who have received at least a first line of systemic anticancer therapy and no more than 2 line of chemotherapy with or without targeted therapy in the metastatic setting and have ECOG performance status ≤ 2. Patients with uncontrolled hypertension and at risk of developing hypertension related complications are not eligible.

Conclusion: FINESSE is a phase II trial testing lucitanib, a multikinase inhibitor, in three selected populations in order to investigate the ORR in FGFR1 or 11q amplified or non-amplified populations and to explore the role of FGFR1 or 11q amplifications through correlative translational analyses. As of May 21st 2015, 40 patients have been enrolled, 19 of them in the FGFR1-amplified arm.